Controlled release dosage form of [R-(Z)]-alpha-(methoxyimino)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride

ABSTRACT

A controlled release formulation of an acetonitrile compound and its use in the treatment and/or prophylaxis of certain disorders.

[0001] The present invention relates to a novel formulation, and to itsuse in the treatment and/or prophylaxis of certain disorders.

[0002] [R-(Z)]-α-(methoxyimino)-α-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile monohydrochloride (compound X) and methodsfor its preparation are disclosed in EP-A-0392803, WO95/31456 andWO93/17018. The compound enhances acetylcholine function via an actionat muscarinic receptors within the central nervous system and istherefore of potential use in the treatment and/or prophylaxis ofdementia in mammals.

[0003] WO96/12486 discloses the use of compound X in the manufacture ofa medicament for enhancing amyloid precursor protein processing along anon-amyloidogenic pathway in patients suffering from, or at risk ofdeveloping, Alzheimer's disease.

[0004] Fast-release swallow tablet and oral solution formulations ofcompound X both result in rapid absorption of the compound into thecirculation, and require twice a day dosing for optimal efficacy.

[0005] It has now been surprisingly found that it is possible toformulate compound X, which has very high water solubility and is activeat extremely low doses, in such a way that release is controlled to takeplace over a period of hours. Such a formulation would require dosingonly once a day: this is likely to improve compliance in a patientpopulation characterised by poor memory; it may also reduce side-effectsin case of accidental overdosing.

[0006] Accordingly, the present invention provides a controlled releaseoral dosage form containing compound X, its parent free base or anyother pharmaceutically acceptable salt thereof.

[0007] By controlled release is meant any formulation technique whereinrelease of the active substance from the dosage form is modified tooccur at a slower rate than that from an immediate release product, suchas a conventional swallow tablet or capsule.

[0008] Controlled release includes delayed release wherein release ofthe active substance from the dosage form is modified to occur at alater time than that from a conventional immediate release product. Thesubsequent release of active substance from a delayed releaseformulation may also be controlled to occur at a slower rate.

[0009] Examples of controlled release formulations which are suitablefor incorporating compound X are described in:

[0010] Sustained Release Medications, Chemical Technology Review No.177. Ed. J. C. Johnson. Noyes Data Corporation 1980.

[0011] Controlled Drug Delivery, Fundamentals and Applications, 2ndEdition. Eds. J. R. Robinson, V. H. L. Lee. Marcel Dekker Inc. New York1987.

[0012] Such controlled release formulations are preferably formulated ina manner such that release of compound X is effected throughout thegastro-intestinal tract. and takes place predominantly over the firsteight to twelve hours following ingestion.

[0013] Preferred formulations include wax matrices, swellable and/orgellable polymer or hydrogel matrices, tablets coated with releasecontrolling polymers or waxes and pellets, granules or beads comprisingmatrices or coated with release controlling polymers or waxes and thenformulated as capsules, compressed tablets or suspensions.

[0014] Suitable waxes for matrix formation or release controllingcoating include non-ionic beeswax derivatives such as Gelucire 62/05,50/02 or 50/13 (Gattefosse), glyceryl behenate, other fatty acid mono-,di- or tri-esters of glycerol such as Precirol ATO5 (Gattefosse),microcrystalline wax, hydrogenated castor oil or hydrogenated vegetableoil, long-chain aliphatic alcohols such as stearyl alcohol and camubawax.

[0015] Suitable materials for the formation of hydrogel matrices orswellable and/or gellable polymer matrices may be selected from alkylcelluloses, hydroxyalkylcelluloses, polyvinyl alcohol,polymethacrylates, polymethylmethacrylates, methacrylate/divinylbenzenecopolymers, carboxymethylamide, polyoxyalkylene glycols, polyvinylpyrrolidone and carboxymethyl cellulose. The swellable polymericmaterial in particular may be selected from crosslinked sodiumcarboxymethylcellulose, crosslinked hydroxypropylcellulose, highmolecular weight polyhydroxypropylmethylcellulose, carboxymethylamide,potassium methacrylate/divinylbenzene copolymer, polymethylmethacrylate,crosslinked polyvinylpyrrolidone and high molecular weight polyvinylalcohol. The gellable polymeric material in particular may be selectedfrom methylcellulose, carboxymethylcellulose, low-molecular weighthydroxypropylmethylcellulose, low-molecular weight polyvinvlalcohols,polyoxyethyleneglycols and non-cross-linked polyvinylpyrrolidone. Theswellable and gellable polymeric material in particular may be selectedfrom medium-viscosity hydroxypropylmethylcellulose and medium-viscositypolyvinylalcohols.

[0016] Release controlling polymers include hydrogel polymers such asthose listed above, hydrophobic polymers and enteric, or pH dependent,polymers.

[0017] Suitable materials for the formation of hydrophobic releasecontrolling polymer coatings include alkyl celluloses, which may be usedin the form of latex suspensions such as Surelease (Colorcon) orAquacoat (FMC), and methacrylic acid derivatives, which may be used inthe form of latex suspensions such as Eudragit RS, RL and NE (Rohm).

[0018] Suitable materials for the formation of enteric or pH dependentpolymer coatings include methacrylic acid derivatives, which may be usedin the form of latex suspensions such as Eudragit L and S (Rohm).

[0019] Seal coats, film layers used to separate the various functionallayers of the formulation or to provide a final layer to the outside ofthe formulation. contain suitable materials for film forming such asalkylcelluloses, which may be used in the form of latex suspensions suchas Surelease (Colorcon) or Aquacoat (FMC), and hydroxyalkycellulosessuch as hydroxypropylmethylcellulose (for example Opadry (Colorcon)).

[0020] The formulation may also include plasticisers such as triethylcitrate, dibutyl sebacate or medium chain triglycerides in the releasecontrolling polymer layer.

[0021] Pellet-forming materials include suitable grades ofmicrocrystalline cellulose such as Avicel PH101 (FMC).

[0022] Granules may be formed from any of the commonly usedpharmaceutical fillers or diluents such as lactose, lactose monohydrate,mannitol, microcrystalline cellulose, dicalcium phosphate or starch.

[0023] Beads may be formed by layering or spraying on non-pareil seeds.

[0024] Other suitable ingredients in controlled-release dosage formsinclude polyethylene glycol and propylene glycol and these, as well asthe pharmaceutical fillers, may be used to modify the release rate byinclusion in matrices, pellets, granules or beads.

[0025] The formulation may also include hydrophobic excipients thatretard the release from the formulation such as ethylcellulose, talc,colloidal silicon dioxide or glyceryl monostearate and/or one or morebinders such as hydroxypropylmethylcellulose, microcrystalline celluloseor polyvinylpyrrolidone.

[0026] Wetting agents such as sodium lauryl sulphate, lubricants such asmagnesium stearate and glidants such as colloidal silica may also beincluded.

[0027] A particularly preferred formulation comprises drug-layered beadscoated with a release controlling polymer either alone or in combinationwith drug-layered beads not coated with a release controlling polymer(immediate release beads). In the drug layering process onto non-pareilbeads, appropriate size non-pareil sugar beads may be layered with asolution or dispersion containing the active substance, inertexcipients, and/or retardants such as ethylcellulose, talc, colloidalsilicon dioxide or glyceryl monostearate and/or one or more binders suchas hydroxypropylmethylcellulose or polyvinylpyrrolidone. The layering ofthe active substance may be accomplished at a predetermined rate andtemperature using either a coating pan or a fluid bed drier. The layeredbeads may be seal coated with a suitable film forming polymer such ashydroxypropylmethylcellulose (e.g. Opadry) or Eudragit® L30D-55 (amethacrylic acid copolymer) and then may be coated with one or moresuitable release controlling polymers preferably selected from fromalkyl celluloses, hydroxyalkylcelluloses, sodium carboxymethyl celluloseand methacrylic acid derivatives, such as ethylcellulose, Eudragit® RS,Eudragit® RL dr Methocel E4M, to produce beads that release compound Xover an eight to twelve hour period and/or release compound X in one ormore pulses. Seal coated beads may be used for an immediate releasedose. The controlled release or a mixture of controlled release andimmediate release beads may then be filled into an appropriate sizecapsule or compressed with inert excipients into tablets of appropriatephysical parameters such as shape, size, hardness and disintegration.The polymer(s), release controlling plus any seal coat polymer(s),preferably make up 10 to 30% by weight of the total dosage form.Plasticizer is normally present and may make up at least 2% by weight.Binder(s) and retardant(s) typically make up to 3-10% by weight.

[0028] Another particularly preferred formulation comprises a swellableand/or gellable polymer matrix tablet. The polymer matrix is preferablya hydrogel polymer selected from alkyl celluloses such asmethylcellulose, hydroxyalkylcelluloses such as hydroxypropylcelluloseand hydroxypropylmethylcellulose, polyvinyl alcohol, polymethacrylates,cross-linked polyvinylpyrrolidone and sodium carboxymethyl cellulose.The polymers typically make up 10 to 50% by weight of the tablet. Thematrix tablet can be sealed with a hydrophobic release controllingpolymer coating such as ethylcellulose (Surelease (Colorcon)) to retardthe hydration of the hydrogel matrix in the tablet. The hydrophobiccoating polymer typically make up 4 to 10% by weight of the tablet.

[0029] Such matrix tablet formulations can be prepared by either directcompression or wet granulation processes. Coating may be accomplishedusing a coating pan.

[0030] Other preferred formulations are described in U.S. Pat. No.5,422,123.

[0031] Thus, a particular aspect of the invention provides a system forthe controlled release of an active substance which is compound X, itsparent free base or any other pharmaceutically acceptable salt thereof,comprising (a) a deposit-core comprising an effective amount of theactive substance and having defined geometric form, and (b) asupport-platform applied to said deposit-core, wherein said deposit-corecontains at least the active substance, and at least one member selectedfrom the group consisting of (1) a polymeric material which swells oncontact with water or aqueous liquids and a gellable polymeric materialwherein the ratio of the said swellable polymeric material to saidgellable polymeric material is in the range 1:9 to 9:1, and (2) a singlepolymeric material having both swelling and gelling properties, andwherein the support-platformn is an elastic support, applied to saiddeposit-core so that it partially covers the surface of the deposit-coreand follows changes due to hydration of the deposit-core and is slowlysoluble and/or slowly gellable in aqueous fluids.

[0032] The swellable polymeric material in (1) may be selected fromcrosslinked sodium carboxymethylcellulose, crosslinkedhydroxypropylcellulose, high molecular weightpolyhydroxypropyl-methylcellulose, carboxy-methyl starch, potassiummethacrylate/divinylbenzene copolymer, crosslinked polyvinylpyrrolidoneand polyvinyl alcohol. The gellable polymeric material in (1) may beselected from methylcellulose and non-cross-linked polyvinylpyrrolidone.

[0033] The support-platform may comprise; polymers such aspolyhydroxypropylmethylcellulose, polyvinyl alcohol, polyacrylate,polymethacrylate, polyhydroxpropyl cellulose and polysodiumcarboxymethylcellulose; plasticizers such as polyoxyethylene glycols,castor oil, hydrogenated cator oil, ethyl phthalate, butyl phthalate,natural glycerides, synthetic glycerides and semisynthetic glycerides;binders such as polyvinylpyrrolidone, methylcellulose, ethyl cellulosegum arabic and alginic acid; hydrophilic agents such as mannitol,lactose, starch and colloidal silica; and/or hydrophobic agents such ashydrogenated castor oil, magnesium stearate, a fatty substance, wax,natural glycerides and synthetic glycerides. The polymer(s) typicallymake up 30 to 90% by weight of the support-platform, for example about35 to 40%. Plasticizer may make up at least 2% by weight of thesupport-platform, for example about 15 to 20%. Binder(s), hydrophilicagent(s) and hydrophobic agent(s) typically total up to about 50% byweight of the support-platform, for example about 40-to 50%.

[0034] Such formulation may be prepared as generally described in U.S.Pat. No. 5,422,123.

[0035] U.S. Pat. No. 4,839,177 discloses a further alternativecontrolled release formulations suitable for use in the presentinvention.

[0036] Thus a further aspect of the invention provides a system for thecontrolled-rate release of compound X, consisting of:

[0037] a) a deposit-core comprising effective amounts of compound X andhaving defined geometric form,

[0038] b) a support-platform applied to said deposit-core wherein saiddeposit-core contains, mixed with the active substance, at least onemember selected from the group consisting of a (a) 5-80% by weight ofthe total weight of deposit-core of a polymeric material having a highdegree of swelling on contact with water or aqueous liquids and 90-10%by weight of the total weight of the deposit core of a gellablepolymeric material, and (b) a single polymeric material having bothswelling and gelling properties, and other adjuvants able to provide themixture with suitable characteristics for compression and for intake ofwater, and wherein said support-platform consists of a polymericmaterial insoluble in aqueous liquids and partially coating said depositcore.

[0039] The swellable polymeric material in (a) may be selected fromcrosslinked sodium carboxymethylcellulose, crosslinkedhydroxypropylcellulose, high molecular weightpolyhydroxypropyl-methylcellulose, carboxy-methylamide, potassiummethacrylate/divinylbenzene copolymer, polymethylmethacrylate,crosslinked polyvinylpyrrolidone and high molecular weight polyvinylalcohol. The gellable polymeric material in (a) may be selected frommethylcellulose, carboxymethylcellulose, low-molecular weighthydroxypropylmethylcellulose, low-molecular weight polyvinylalcohols,polyoxyethyleneglycols and non-cross-linked polyvinylpyrrolidone. Theswellable and gellable polymeric material in (b) may be selected frommedium-viscosity hydroxypropylmethylcellulose and medium-viscositypolyvinylalcohols. The support platform may comprise insoluble polymericmaterial selected from acrylates, cellulose, ethylcellulose, celluloseacetate-propionate, polyethylene, methacrylates, acrylic acid copolymersand high-molecular weight polyvinylalcohols.

[0040] Such formnulation may be prepared as generally described in U.S.Pat. No. 4,839,177.

[0041] WO 94/06416 discloses a yet further alternative controlledrelease formulations suitable for use in the present invention.

[0042] Thus a yet further aspect of the invention provides a system forthe controlled-rate release of compound X, consisting of apharmaceutical compressed tablet capable of releasing compound X atdifferent rates, consisting of three layers, wherein

[0043] a first layer contains compound X with immediate or controlledrelease formulation, composed of rapidly swelling and/or soluble and/orerodible polymeric substances by contact with aqueous fluids, andadjuvants;

[0044] a second layer contains compound X, either equal to or differentfrom those of the first layer, with slow release formulation, composedof swelling and/or gellable and/or erodible polymeric substances bycontact with aqueous fluids, and adjuvants;

[0045] a low-permeability barrier-type layer coating said second layeror, alternatively, placed between the first and second layer, consistingof polymeric substances, adjuvants, plasticizing agents and, ifnecessary, compound X.

[0046] The polymeric substances of the first layer may be selected fromcross-linked polyvinylpyrrolidone, low- and medium-molecular-weighthydroxypropyl cellulose and hydroxypropyl methylcellulose, cross-linkedsodium carboxymethylcellulose, carboxymethyl starch, potassiummethacrylate-divinylbenzene copolymer, polyvinyl alcohols, starches,starch derivatives, microcrystalline cellulose and cellulosederivatives, β-cyclodextrin and dextrin derivatives.

[0047] The polymeric substances of the second layer may be selected fromthe group consisting of hydroxypropyl methylcellulose having molecularweight from 1,000 to 4,000,000, hydroxypropyl cellulose having molecularweight from 2,000 to 2,000,000, carboxyvinyl polymers, polyvinylalcohols, glucans, scleroglucans, mannans, xanthans, alginic acid andderivatives thereof, carboxymethylcellulose and derivatives thereof,poly(methyl vinyl ethers/maleic anhydride), ethylcellulose,methylcellulose, and cellulose derivatives.

[0048] The adjuvants of the first and second layers may be selected fromthe group consisting of starch, pregelled starch, calcium phosphate.mannitol, lactose, saccharose, glucose, sorbitol, microcrystallinecellulose, gelatin, polyvinylpyrrolidone, methylcellulose, starchsolution, ethylcellulose, arabic gum, tragacanth gum, magnesiumstearate, stearic acid, colloidal silica, glyceryl monostearate,hydrogenated castor oil, waxes, and mono-, bi-, and trisubstitutedglycerides.

[0049] The polymeric substances of the barrier type layer may beselected from the group consisting of hydroxypropyl methylcellulosehaving molecular weight from 1,000 to 4,000,000, hydroxypropyl cellulosehaving molecular weight from 2,000 to 2,000.000, carboxyvinyl polymers,polyvinyl alcohols, glucans, scleroglucans, mannans, xanthans,carboxymethylcellulose, ethylcellulose, and methylcellulose.

[0050] The adjuvants of the barrier-type layer may be selected from thegroup consisting of glyceryl monostearate, semisynthetic glycerides,glyceryl palmitostearate, glyceryl behenate, polyvinylpyrrolidone,gelatine, ethylcellulose, methylcellulose, sodiumcarboxymethylcellulose, magnesium stearate, stearic acid, sodiumstearate, talc, sodium benzoate, boric acid, and colloidal silica.

[0051] The plasticizing agents of the barrier-type layer may be selectedfrom the group consisting of hydrogenated castor oil, fatty acids,substituted triglycerides and glycerides, polyoxyethylene glycols andderivatives thereof having molecular weight from 400 to 60,000.

[0052] Such formulation may be prepared as generally described in WO94/06416.

[0053] The dosage form preferably contains compound X itself.

[0054] Compound X has active doses around 5-125 microgramme (μg)(calculated as free base). It has been found through administration tohuman patients that efficacy as a cognition enhancer may be obtained atdaily doses below 0.01 mg/kg more particularly 0.003 mg/kg and below,for example 0.0001-0.003 mg/kg, such as 0.00035-0.003 mg/kg,0.0007-0.003 mg/kg, 0.0001-0.0007 mg/kg or 0.00035-0.002 mg/kg.

[0055] Suitable unit doses to achieve such daily doses are 5, 12.5, 25,50 or 75 μg, administered twice daily or 50 μg or 100 μg, once daily.Such unit doses are calculated on the basis of 50-70 μg individuals andas free base.

[0056] Suitably, the in vitro release profile of the dosage form i.e.the amount of compound X released over time will be selected so that itwill provide an area under the in vivo plasma profile curve that issimilar to that obtained following conventional oral administration of afast release tablet, 5 to 75 μg (calculated as free base) compound Xtwice a day. Preferably 25-70% is released over 4hours and 70-100% isreleased over 8 hours.

[0057] The dosage form of the invention may be used in the treatmentand/or prophylaxis of dementia, including Alzheimer's disease, inmammals, and for enhancing amyloid precursor protein processing along anon-amyloidogenic pathway in patients suffering from, or at risk ofdeveloping, Alzheimer's disease. These disorders are herein afterreferred to as “the Disorders”.

[0058] The present invention provides a method of treating “theDisorders” by administering an effective amount of a controlled releaseoral dosage form containing compound X, its parent free base or anyother pharmaceutically acceptable salt thereof, to a sufferer in needthereof.

[0059] The present invention further provides the use of a controlledrelease oral dosage form containing compound X, its parent free base orany other pharmaceutically acceptable salt thereof, in the manufactureof a medicament for treating “the Disorders”.

[0060] The present invention also provides a pharmaceutical compositionfor use in the treatment of “the disorders” which comprises a controlledrelease oral dosage form containing compound X, its parent free base orany other pharmaceutically acceptable salt thereof.

[0061] The following examples illustrate the present invention.

EXAMPLES

[0062] In the following examples, the weight shown is the weight of freebase; compound X is the hydrochloride salt. (pfb=pure free base). Meshsizes are US standard.

Example 1 (Wax matrix)

[0063] Compound X 0.005-0.1 mg pfb Gelucire 62/05 (Gattefosse) 190 mgPropylene glycol  10 mg

Example 2 Film Coated Pellets

[0064] Component mg/capsule (500 mg) Function Compound X 0.005-0.1 mgpfb Active Lactose 300 Hydrophilic diluent Avicel PH 101 (FMC) 200 Inertpellet matrix Film coat: w/w of pellet cores Surelease (Colorcon) 2-10%Release controlling polymer coat Silicone antifoam Antifoaming agent

Example 3 Film Coated Pellets

[0065] Component mg/capsule (500 mg) Function Compound X 0.005-0.1 mgpfb Active Lactose 400 Hydrophilic diluent Avicel PH 101 100 Inertpellet matrix Film coat: w/w of pellet cores Aquacoat (FMC)  2-10%Release controlling polymer coat Silicone antifoam Antifoaming agentDi-butylsebacate 20-30% (of polymer Plasticizer weight)

[0066] In Examples 2 and 3, pellets are produced byextrusion/spheronization, using water as a granulation liquid and anappropriate size fraction is obtained by screening. Pellets are thencoated in a fluid bed coater (bottom spray) with 2-10% (w/w) of anaqueous Surelease dispersion (15% solids in dispersion).

[0067] Desired release profiles are obtained by mixing uncoated(=immediate release pellets) and coated pellets of suitable coatinglevels (=sustained release pellets), that are then filled into hardgelatine capsules.

Example 4 Matrix Pellets

[0068] Component mg/capsule (500 mg) Function Compound X 0.005-0.1 mgpfb Active Glyceryl behenate 200 Hydrophobic matrix Avicel PH 101 300Inert pellet matrix Sodium lauryl sulphate  0.1 Wetting agent

[0069] Pellets are produced by extrusion/spheronization using water andsodium laurylsulphate as a granulation liquid, and an appropriate sizefraction is obtained by screening. Pellets may additionally be coated ina fluid bed coater (bottom spray) with aqueous polymer dispersions tofurther reduce release rates and obtain the desired release profiles.

Example 5 Hydrogel Matrix

[0070] Excipient % w/w mg/tablet mg/tablet Compound X 0.003-0.07 pfb0.005 pfb 0.1 pfb Hydroxypropylcellulose 25 37.5 37.5 Purified water — —— Starch to 100 109.5 108.5 Magnesium stearate 2 3.0 3.0 Total 100 150150

[0071] Tablets may be prepared by the following procedure:

[0072] 1. Blend the starch and HPC in a high shear mixer

[0073] 2. Dissolve the drug into a small quantity of water and sprayinto blend while mixing

[0074] 3. Wash spray mechanism with small volume of water into blendwhile mixing

[0075] 4. Granulate mix with sufficient water to achieve a medium toheavy granule

[0076] 5. Partially dry granule

[0077] 6. Screen through a suitable mill

[0078] 7. Complete drying of milled granule

[0079] 8. Lubricate with Mg stearate

[0080] 9. Compress into tablets with a target weight of 150 mg

Example 6 Wax Matrix

[0081] Excipient % w/w mg/tablet mg/tablet Compound X 0.003 to 0.07 pfb0.005 pfb 0.1 pfb Lactose Anhydrous to 100 to 150 to 150 Gelucire 62/0518 27.0 27.0 Magnesium stearate 2 3.0 3.0 Total 100 150 150

[0082] Tablets may be prepared by the following procedure:

[0083] 1. Preblend the drug with a small quantity of lactose

[0084] 2. Sandwich the drug preblend with the remaining lactose and therequired % of Gelucire 62/05 in a preheated pelletiser.

[0085] 3. Pelletise until the required pellet size has been achieved

[0086] 4. Remove the pellets and allow them to cool

[0087] 5. Screen pellets as necessary

[0088] 6. Lubricate pellets

[0089] 7. Compress or encapsulate pellets

Example 7 Controlled Release Bilayer Tablet

[0090] mg/tablet Function Active Layer Component Compound X 0.005-0.1 mgpfb Active Hydroxypropylmethylcellulose 68.5 Hydrogel matrix formerMannitol 20 Soluble filler Ethyl cellulose (applied in 7.5 Binderethanolic solution) Magnesium stearate 2 Lubricant Colloidol silica 2Glidant Support platform Component Hydroxypropylmethylcellulose 39.75Hydrogel matrix former Hydrogenated castor oil 6.5 Insoluble fillerEthylcellulose (applied in 2.5 Binder ethanolic solution) Yellow ironoxide pigment 0.5 Pigment Magnesium stearate 0.5 Lubricant Colloidalsilica 0.25 Glidant

Example 8 Wax Matrix

[0091] Component % w/w Function Compound X 0.02 pfb Active Gelucire50/02 91.5 Wax matrix Gelucire 50/13 5 Wax matrix Propylene glycol 1.98Solvent Colloidal silica 1.5 Hydrophobic excipient Sodium dihydrogencitrate   0-1.5 Stabilizer

[0092] Process

[0093] The Gelucire waxes were melted together at around 60 degrees C.Compound X was dissolved in propylene glycol, and blended into thewaxes. The colloidal silica was then also blended in, and the mixturefilled into size 3 hard gelatin capsule shells. TABLE 1 Release Profileof wax-filled capsules of Compound X in water (0% citrate) Time (hr) %Released 1 13 3 29 5 53 8 73

Example 9 Ethylcellulose Coated Beads

[0094] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 meshsize may be used. A medicated layer solution of the followingcomposition was used: Component % w/w Function Compound X 0.003-0.05 pfbActive Opadry ® Clear 3 Binder Sodium dihydrogen citrate 1.5 StabilizerPurified water q.s. Total 100

[0095] Seal coating solution: A solution of Opadry® Clear (YS-1-9025A)in purified water at 10% solids concentrations was made by dissolving100 grams of Opadry® Clear into 900 grams of purified water.

[0096] Polymer Coating: A polymer coating dispersion containingethylcellulose (Surelease®) of the following composition was made andused for polymer coating the seal coated beads at an 10% to 25% weightgain, in particular 10, 12, 15, 17, 22 and 25%. Component % w/w FunctionSurelease ® 60 (25% as solids) Release controlling polymer coat withplasticiser Purified water q.s. Total 100

[0097] Drug layered beads were produced by layering the drug solutiononto 25-30 mesh non-pareil beads using a Niro STREA-1 fluid bed dryer soas to layer 100 micrograms of the drug as the free base onto 200 mg ofthe non-pareil beads. The drug layered beads were seal coated withOpadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beadswere polymer coated to a weight gain of 10% to 25% with the Surelease®coating dispersion. The final polymer coated beads were produced by sealcoating the polymer coated beads to a weight gain of 2% with the Opadry®Clear seal coating solution. TABLE 2 Release Profile Range ofEthylcellulose coated beads, 10-25% by weight of Compound X in WaterTime (hr) % Released 1 0.8-36  2  5-57 4 13-75 8 18-91

Example 10 Ethylcellulose Coated Beads

[0098] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 meshsize may be used. A medicated layer solution of the followingcomposition was used: Component % w/w Function Compound X 0.003-0.05pfbActive Opadry ® Clear 3 Binder Sodium dihydrogen citrate 1.5 StabilizerPurified water q.s. Total 100

[0099] Seal coating: A seal coating dispersion containing Eudragit®L30D-55 of the following composition was made and used for seal coatingthe drug layered beads at an 4% weight gain. Component % w/w FunctionEudragit ® L30D-55 45 (30% as solids) Polymeric seal coat Triethylcitrate 2.02 Plasticizer Talc 3.10 Anti-tack Purified water q.s. Total100

[0100] Polymer Coating: A polymer coating dispersion containingethylcellulose (Surelease®) of the following composition was made andused for polymer coating the seal coated beads at an 10% to 25% weightgain. Component % w/w Function Surelease ® 60 (25% as solids) Releasecontrolling polymer coat with plasticiser Purified water q.s. Total 100

[0101] Drug layered beads were produced by layering the drug solutiononto 25-30 mesh non-pareil beads using a Niro STREA-1 fluid bed dryer soas to layer 100 micrograms of the drug as the free base onto 200 mg ofthe non-pareil beads. The drug layered beads were seal coated withEudragit® L30D-55 seal coating dispersion to a weight gain of 4% toproduce the immediate release beads. A portion of the immediate releasebeads were polymer coated to a weight gain of 10% tp 25% with theSurelease® coating dispersion. The final polymer coated beads wereproduced by seal coating the polymer coated beads to a weight gain of 2%with the Opadry® Clear seal coating solution. TABLE 3 Release Profile ofEudragit ® L30D Seal Coated/Ethylcellulose Coated Beads of Compound X inWater Time (hr) % Released, 10% Surelease 0.5 1.5 1 5 2 20 4 39 6 49 856

Example 11 Ethylcellulose Coated Beads

[0102] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 meshsize may be used. A medicated layer solution of the followingcomposition was used: Component % w/w Function Compound X 0.003-0.05pfbActive Opadry ® Clear 3 Binder Sodium dihydrogen citrate 1.5 StabilizerPurified water q.s. Total 100

[0103] Seal coating solution: A solution of Opadry® Clear (YS-1-9025A)in purified water at 10% solids concentrations was made by dissolving100 grams of Opadry® Clear into 900 grams of purified water.

[0104] Polymer Coating: A polymer coating dispersion containingEthylcellulose (Aquacoat®) of the following composition was made andused for polymer coating the seal coated beads at a 10% weight gain.Component % w/w Function Aquacoat ® 50 (30% as solids) Releasecontrolling polymer coat Triethyl Citrate 2.02 Plasticizer Purifiedwater q.s. Total 100

[0105] Drug layered beads were produced by layering the drug solutiononto 25-30 mesh non-pareil beads using a Niro STREA-1 fluid bed dryer soas to layer 100 micrograms of the drug as the free base onto 200 mg ofthe non-pareil beads. The drug layered beads were seal coated withOpadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beadswere polymer coated to a weight gain of 10% with the Aquacoat® coatingdispersion. The final polymer coated beads were produced by seal coatingthe polymer coated beads to a weight gain of 2% with thie Opadry® Clearseal coating solution.

Example 12 Eudragit Coated Beads

[0106] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 meshsize may be used. A medicated layer solution of the followingcomposition was used: Component % w/w Function Compound X 0.003-0.05pfbActive Opadry ® Clear 3 Binder Sodium dihydrogen citrate 1.5 StabilizerPurified water q.s. Total 100

[0107] Seal coating solution: A solution of Opadry® Clear (YS-1-9025A)in purified water at 10% solids concentrations was made by dissolving100 grams of Opadry® Clear into 900 grams of purified water.

[0108] Polymer Coating: A polymer coating dispersion containinggudragit® RS or RS/RL of the following composition was made and used forpolymer coating the seal coated beads at an 10% weight gain. Component %w/w Function Eudragit ® RS 30D 45 (30% as solids) Release controllingpolymer coat Triethyl citrate 2.02 Plasticizer Talc 3.10 Anti-tackPurified water q.s. Total 100 or Eudragit ® RS 30D 36 (30% as solids)Release controlling polymer coat Eudragit ® RL 30D  9 (30% as solids)Release controlling polymer coat Triethyl citrate 2.02 Plasticizer Talc3.10 Anti-tack Purified water q.s. Total 100

[0109] Drug layered beads were produced by layering the drug solutiononto 25-30 mesh non-pareil beads using a Niro STREA-1 fluid bed dryer soas to layer 100 micrograms of the drug as the free base onto 200 mg ofthe non-pareil beads. The drug layered beads were seal coated withOpadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beadswere polymer coated to a weight gain of 10% with the Eudragit® RS orRS/RL coating dispersion. The final polymer coated beads can be producedby seal coating the polymer coated beads to a weight gain of 2% with theOpadry® Clear seal coating solution. TABLE 4 Release Profile ofEudragit ® RS/RL coated beads of Compound X in water Time (hr) %Released 0.5 0.2 1 0.3 2 0.4 4 1.9 6 13 8 20

Example 13 Methocel Coated Beads

[0110] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 meshsize may be used. A medicated layer solution of the followingcomposition was used: Component % w/w Function Compound X 0.003-0.05pfbActive Methocel E4M 15 Release controlling polymer coat Sodiumdihydrogen citrate 1.5 Stabilizer Purified water q.s. Total 100

[0111] Seal coating solution: A solution of Opadry® Clear (YS-1-7006) inpurified water at 10% solids concentrations was made by dissolving 100grams of Opadry® Clear into 900 grams of purified water.

Example 14 Ethylcellulose Coated Beads with a Retardant

[0112] 200 mg of non-pareil sugar beads of 16-20, 20-25 or 25-30 meshsize may be used. A medicated layer solution of the followingcomposition was used: Component % w/w Function Compound X 0.003-0.05pfbActive Opadry ® Clear 1.5 Binder Surelease ® 1.5 Retardant Sodiumdihydrogen citrate 1.5 Stabilizer Purified water q.s. Total 100

[0113] Seal coating solution: A solution of Opadry® Clear (YS-1-9025A)in purified water at 10% solids concentrations was made by dissolving100 grams of Opadry® Clear into 900 grams of purified water.

[0114] Polymer Coating: A polymer coating dispersion containingEthylcellulose (Surelease®) of the following composition was made andused for polymer coating the seal coated beads at 10% weight gain.Component % w/w Function Surelease ® 60 (25% as solids) Releasecontrolling polymer coat with plasticiser Purified water q.s. Total 100

[0115] Drug layered beads were produced by layering the drug solutiononto 25-30 mesh non-pareil beads using a Niro STREA-1 fluid bed dryer soas to layer 100 micrograms of the drug as the free base ontc 200 mg ofthe non-pareil beads. The drug layered beads were seal coated withOpadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beadswere polymer coated to a weight gain of 10% with the Surelease® coatingdispersion. The final polymer coated beads can be produced by sealcoating the polymer coated beads to a weight gain of 2% with the Opadry®Clear seal coating solution. TABLE 5 Release Profile of EthylcelluloseCoated Beads, with Retardant, of Compound X in Water % Released Time(hr) Without Retardant With Retardant 0.5 12  8 1 37 22 2 57 35 4 73 486 85 53 8 58

Example 15 Enteric Coated Beads)

[0116] 200 mg of non-pareil sugar beads of 16-20,20-25 or 25-30 meshsize may be used. A medicated layer solution of the followingcomposition was used: Component % w/w Function Compound X 0.003-0.05pfbActive Opadry ® Clear 3 Binder Sodium dihydrogen citrate 1.5 StabilizerPurified water q.s. Total 100

[0117] Seal coating solution: A solution of Opadry® Clear (YS-1-9025A)in purified water at 10% solids concentrations was made by dissolving100 grams of Opadry® Clear into 900 grams of purified water.

[0118] Polymer Coating: A nolymer coating dispersion containingEudragit® L30D-55 of the following composition was made and used forpolymer coating the seal coated beads at an 20% weight gain. Component %w/w Function Eudragit L30D-55 45.00 (30% as solids) Enteric (pHdependent) polymer Triethyl citrate 2.02 Plasticizer Talc 3.10 Anti-tackPurified water q.s. Total 100

[0119] Drug layered beads were produced by layering the drug solutiononto 25-30 mesh non-pareil beads using a Niro STREA-1 fluid bed dryer soas to layer 100 micrograms of the drug as the free base onto 200 mg ofthe non-pareil beads. The drug layered beads were seal coated withOpadry® Clear seal coating solution to a weight gain of 3% to producethe immediate release beads. A portion of the immediate release beadswere enteric coated to a weight gain of 20% with the Eudragit® entericcoating dispersion. The final enteric coated beads were produced by sealcoating the enteric coated beads to a weight gain of 2% with the OpadryClear seal coating solution.

Example 16 Matrix Tablet

[0120] Ingredient mg/tablet Function Compound X 0.005-0.1 pfb ActiveHydroxpropyl Methcellulose 75.0 Hydrogel matrix E4M CR Sodium DihydrogenCitrate 3.00 Stabilizer Lactose, Fast Flo 70.38 Hydrophilic diluentMagnesium Stearate 1.50 Lubicant Opadry ® White 2.25 Seal coat polymer

[0121] Seal coating solution: A solution of Opadry® Clear (YS-1-9025A)in purified water at 10% solids concentrations was made by dissolving100 grams of Opadry® Clear into 900 grams of purified water.

[0122] Polymer Coating: A polymer coating dispersion containingEthylcellulose (Surelease®) of the following composition was made andused for polymer coating the seal coated beads at 10% weight gain.Component % w/w Function Surelease ® 60 (25% as solids) Releasecontrolling polymer coat with plasticiser Purified water q.s. Total 100

[0123] 700 grams of core tablets were coated using a Vector LDCS pan toa 3% weight gain with the Opadry® Clear seal coating solution. The sealcoated tablets were then polymer coated to 4% weight gain using theSurelease® coating dispersion. TABLE 6 Release Profile for a MatrixTablet of Compound X in water Time (hr) % Dissolved 1 8 2 30 4 58 8 96

Example 17 Controlled Release Bilayer Tablet

[0124] mg/tablet Function Active Layer Component Compound X 0.005-0.1 mgpfb Active Methocel K4M 15.00 Hydrogel polymer Lactose monohydrate 62.0Hydrophilic filler Polyvinylpyrrolidone 3.0 Binder Magnesium stearate1.0 Hydrophobic lubricant Syloid 244 1.0 Hydrophilic glidant Supportplatform Component Compritol 888 15.0 Plasticizer Lactose monohydrate29.0 Hydrophilic filler Polyvinylpyrrolidone 4.0 Binder Magnesiumstearate 1.5 Hydrophobic lubricant Methocel E5 29.4 Hydrogel polymerIron oxide 0.1 Colourant

1. A controlled release oral dosage form containing[R-(Z)]-α-(methoxyimino)-α-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrilemonohydrochloride (compound X), its parent free base or any otherpharmaceutically acceptable salt thereof.
 2. A dosage form according toclaim 1 which provides an in vitro release profile selected to providean area under the in vivo plasma profile curve that is similar to thatobtained following conventional oral administration of a fast releasetablet 5 to 75 μg (calculated as free base) compound X twice a day. 3 Adosage form according to claim 1 or 2 which provides an in vitro releaseprofile of 25-70% over 4 hours and 70-100% over 8 hours.
 4. A dosageform according to any of claims 1 to 3 selected from wax matrices,swellable and/or gellable matrices, tablets coated with releasecontrolling polymers or waxes, and pellets, granules or beads comprisingmatrices or coated with release controlling polymers or waxes and thenformulated as capsules, compressed tablets or suspensions.
 5. A dosageform according to any preceding claim comprising a swellable and/orgellable matrix selected from alkyl celluloses, hydroxyalkylcelluloses,polyvinyl alcohol, polymethacrylates, polymethylmethacrylates,methacrylate/divinylbenzene copolymers, carboxymethylamide,polyoxyalkylene glycols, polyvinyl pyrrolidone and carboxymethylcellulose.
 6. A dosage form according to claim 5 wherein the matrix isselected from alkyl celluloses, hydroxyalkylcelluloses, polyvinylalcohol, polymethacrylates, cross-linked polyvinylpyrrolidone and sodiumcarboxymethyl cellulose.
 7. A dosage form according to claim 5 or 6comprising a hydrogel matrix tablet coated with a hydrophobic releasecontrolling polymer coating selected from alkyl celluloses andmethacrylic acid derivatives.
 8. A dosage form according to claim 7wherein the polymer matrix comprises 10-50% and the hydrophobic releasecontrolling polymer comprises 4-10% by weight of the tablet.
 9. A dosageform according to claim 7 or 8 comprising a tablet of the followingcomposition (mg/tablet): Compound X 0.005-0.1 pfb HydroxpropylMethcellulose E4M CR 75.0 Sodium Dihydrogen Citrate    0-3.00 Lactose,Fast Flo 70.38-73.38 Magnesium Stearate  1.50 Opadry ® White  2.25

seal coated with a solution of Opadry® Clear (YS-1-7006) in purifiedwater at 10% solids concentrations and polymer coated with a 60% w/w(25% as solids) dispersion containing Ethylcellulose (Surelease®) at 10%weight gain, formed into core tablets, coated with the Opadry® Clearseal coating solution and polymer coated to 4% weight gain using 60% w/w(25% as solids) dispersion containing Ethylcellulose (Surelease®). - 10.A dosage form according to any of claims 1 to 4 which comprisesdrug-layered beads coated with a release controlling polymer eitheralone or in combination with drug-layered beads not coated with arelease controlling polymer (immediate release beads) and optionally,inert excipients and/or retardants and/or one or more binders.
 11. Adosage form according to claim 10 wherein the layered beads are sealcoated with a film-forming polymer.
 12. A dosage form according to claim10 or 11 wherein the release controlling polymer coating is selectedfrom from alkyl celluloses, hydroxyalkylcelluloses, sodium carboxymethylcellulose and methacrylic acid derivatives.
 13. A dosage form accordingto any of claims 10 to 12 wherein the polymer(s) make up 10 to 30% byweight of the total dosage form.
 14. A dosage form according to claim 10in capsule form comprising non-pareil sugar beads of 16-20, 20-25 or25-30 mesh size, coated to a drug loading of 100 microgrammes(calculated as free base) per 200 mg beads, with a medicated aqueouslayer solution of the following composition (%w/w): Compound X0.003-0.06 pfb Opadry ® Clear 3 Sodium dihydride citrate    0-1.5

seal coated with a solution of Opadry® Clear (YS-1-7006) in purifiedwater at 10% solids concentrations to a weight gain of 3%, and a portionof the beads further polymer coated to a weight gain of 10-25% with a60%w/w (25% as solids) dispersion containing ethylcellulose (Surelease®)and then seal coated to a weight gain of 2% with the above seal coat.15. A method of treatment and/or prophylaxis of dementia, includingAlzheimer's disease, in mammals by administering an effective amount ofa controlled release oral dosage form according to claim 1, to asufferer in need thereof.
 16. A method for enhancing amyloid precursorprotein processing along a non-amyloidogenic pathway in patientssuffering from, or at risk of developing, Alzheimer's disease byadministering an effective amount of a controlled release oral dosageform according to claim 1, to a sufferer in need thereof.
 17. The use ofa controlled release oral dosage form according to claim 1 in themanufacture of a medicament for treatment and/or prophylaxis ofdementia, including Alzheimer's disease, in mammals.
 18. The use of acontrolled release oral dosage form according to claim 1, in themanufacture of a medicament for enhancing amyloid precursor proteinprocessing along a non-amyloidogenic pathway in patients suffering from,or at risk of developing, Alzheimer's disease.
 19. A pharmaceuticalcomposition for treatment and/or prophylaxis of dementia, includingAlzheimer's disease, in mammals which comprises a controlled releaseoral dosage form according to claim
 1. 20. A pharmaceutical compositionfor enhancing amyloid precursor protein processing along anon-amyloidogenic pathway in patients suffering from, or at risk ofdeveloping, Alzheimer's disease which comprises a controlled releaseoral dosage form according to claim
 1. 21. A dosage form, method, use orcomposition according to any preceding claim in which release in thegastro-intestinal tract takes place predominantly over the first-eightto twelve hours following ingestion.
 22. A dosage form, method, use orcomposition according to any preceding claim containing[R-(Z)]-α-(methoxyimino)-α-(1-azabicyclo [2.2.2]oct-3-yl)acetonitrilemonohydrochloride.
 23. A dosage form, method, use or compositionaccording to any of claims 1 to 22 containing 5 μg compound X(calculated as free base).
 24. A dosage form, method, use or compositionaccording to any of claims 1 to 22 containing 12.5 μg compound X(calculated as free base).
 25. A dosage form, method, use or compositionaccording to any of claims 1 to 22 containing 25 μg compound X(calculated as free base).
 26. A dosage form, method, use or compositionaccording to any of claims 1 to 22 containing 50 μg compound X(calculated as free base).
 27. A dosage form, method, use or compositionaccording to any of claims 1 to 22 containing 75 μg compound X(calculated as free base).
 28. A dosage form, method, use or compositionaccording to any of claims 1 to 22 containing 100 μg compound X(calculated as free base).